Paget's disease of bone is a disorder of an unknown cause in which bone resorption is abnormally increased at pelvis, femur, skull and the like so that symptoms such as bone deformity and bone pain develop. Therapeutic agents of Paget's disease of bone that are currently in use are bisphosphonates formulations and calcitonin formulations, which are also used as a therapeutic agent of osteoporosis. However, both formulations have drawbacks in that the former have poor compliance because they require a dosage that is 4 to 5 times larger than that used against osteoporosis patients and the latter cannot exert a sufficient inhibitory action on bone resorption. Furthermore, these formulations cannot completely core the disease because they are symptomatic treatment agents based on an inhibitory action on bone resorption. Recently, it has been found that osteoclast precursor cells collected from patients with Paget's disease of bone have a 1α, 25-dihydroxy vitamin D3 receptor and that the responsitivity of the cells to 1α, 25-dihydroxy vitamin D3 has increased by a factor of 10 to 100 compared to osteoclast precursor cells collected from normal individuals (J. Bone Miner. Res., Vol. 15, 228-236, 2000). In addition, it has been assumed that increased bone resorption by endogenous 1α, 25-dihydroxy vitamin D3 plays a key role in the development of Paget's disease of bone, as 1α, 25-dihydroxy vitamin D3 in the blood of patients with Paget's disease of bone is present at the same concentration as in the blood of normal individuals. Consequently, a compound which suppresses the action of 1α, 25-dihydroxy vitamin D3 on osteoclast precursor cells, that is, a compound like a vitamin D antagonist may more fundamentally suppress increased bone resorption of patients with Paget's disease of bone and can be expected to have a therapeutic effect superior to current bone resorption suppressors.
On the other hand, hypercalcemia is developed by increased vitamin D production associated with various diseases, for example, lymphoma (Blood, Vol. 73, 235-239, 1989; Blood, Vol. 82, 1383-1394, 1993), tuberculosis (N. Engl. J. Med., Vol. 311, 1683-1685, 1984), sarcoidosis (J. Clin. Endocrinol. Metab., Vol. 60, 960-966, 1985), candida (Am. J. Med., Vol. 74, 721-724, 1983), granuloma (N. Engl. J. Med., Vol. 311, 1103-1105, 1984; Am. J. Nephrol., Vol. 13, 275-277, 1993; Am. J. Med. Sci., Vol. 301, 178-181, 1991), leprosy (Ann. Intern Med., Vol. 105, 890-891, 1986), primary hyperparathyroidism, malignant tumors and the like. As the level of calcium in the blood is known to be increased by the action of active form of vitamin D3, a compound antagonistic to active form of vitamin D3, that is, a vitamin D3 antagonist is believed to be effective for the treatment of hypercalcemia.
The prior art relating to compounds of the present invention is the following. The specification of International Publication WO 95/33716 describes compounds having an α-methylene lactone structure as a D-ring side-chain of vitamin D3. However, none of these compounds are included in the compounds of the present invention, and no descriptions or suggestions have been made in the specification whether the compounds described have a vitamin D3 antagonist action or not. Furthermore, there is a description in J. Biol. Chem. Vol. 274, 16392-16399, 1999 and J. Biol. Chem. Vol. 274, 32376-32381, 1999 indicating that the compounds described in the above specification of International Publication WO 95/33716 have a vitamin D3 antagonist action. These compounds are, however, not included in the compounds of the present invention. Also, in the specification of WO 00/24712, there is disclosed compounds that have an α-methylene-cycloalkanone structure as a side chain of the D-ring of vitamin D3. Additionally, the publication of Japanese Unexamined Patent Application No. 11-116551 and the specification of International Publication WO 98/50353 disclose compounds having a methyl group as a substituent at 2-position of vitamin D3. However, the compounds described in these application specifications have a 1α, 25-dihydroxy vitamin D3 structure (6-hydroxy-6-methylheptan-2-yl) as the D-ring side-chain of vitamin D3, which are different from the compounds having an α-methylene-lactone structure disclosed in the present invention. Moreover, there are neither descriptions nor suggestions in the specifications whether the described compounds have a vitamin D3 antagonist action or not.